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					Radiol Oncol 2005; 39(3): 197-210.



review

                         Molecular biology of the lung cancer


                                               Sasho Z. Panov

       Laboratory for Molecular Biology, Institute of Biology, Faculty of Natural Sciences and
        Mathematics, “Ss. Cyril and Methodius” University, Skopje, Republic of Macedonia



Background. Lung cancer is one of the most common malignant diseases and leading cause of cancer death
worldwide. The advances in molecular biology and genetics, including the modern microarray technology
and rapid sequencing techniques, have enabled a remarkable progress into elucidating the lung cancer
ethiopathogenesis.
Numerous studies suggest that more than 20 different genetic and epigenetic alterations are accumulating
during the pathogenesis of clinically evident pulmonary cancers as a clonal, multistep process. Thus far, the
most investigated alterations are the inactivational mutations and losses of tumour suppressor genes and the
overexpression of growth-promoting oncogenes. More recently, the acquired epigenetic inactivation of tu-
mour suppressor genes by promoter hypermethylation has been recognized. The early clonal genetic abnor-
malities that occur in preneoplastic bronchial epithelium damaged by smoking or other carcinogenes are be-
ing identified. The molecular distinctions between small cell lung cancer (SCLC) and non-small cell lung can-
cer (NSCLC), as well as between tumors with different clinical outcomes have been described. These inves-
tigations lead to the “hallmarks of lung cancer”.
Conclusions. It is realistic to expect that the molecular and cell culture-based investigations will lead to discov-
eries of new clinical applications with the potential to provide new avenues for early diagnosis, risk assessment,
prevention, and most important, new more effective treatment approaches for the lung cancer patients.

Key words: lung neoplasms-genetics; genes, tumor suppressor


                    Introduction                            death worldwide with estimated more than 1.3
                                                            million new cases each year.1 The lung cancer
Lung cancer is one of the most common ma-                   incidence and mortality have risen into epi-
lignant diseases and leading cause of cancer                demic proportions in Western world during
                                                            the 20th century.2 The majority of lung cancer
Received 24 August 2005
                                                            patients is inoperable or has disseminated dis-
Accepted 11 September 2005
                                                            ease at the time of diagnosis and displays a re-
Correspondence to: Sasho Z. Panov, PhD, Teaching            markable insensitiveness to chemotherapeu-
and Research Assistant of Molecular Biology and             tics and radiation therapy.3 Over 85% of these
Molecular Genetics, Institute of Biology, Faculty of        patients eventually die from disseminated dis-
Natural Sciences and Mathematics, “Ss. Cyril and
Methodius” University, Arhimedova bb., MK-1000,             ease during the first 5 years and this extreme
Skopje, Republic of Macedonia; Phone: 389 70 248            mortality has not changed significantly during
790; Fax: 389 2 3228 141; E-mail: sasho@mt.net.mk           the last three decades. Despite diagnostic and
198                                  Panov SZ / Molecular biology of the lung cancer



therapeutic improvements, the 5-year survival                  of multiple molecular abnormalities over
rate has barely increased from 7 to 14% since                  time. Those alterations lead to acquired cellu-
1970-thies to the present. Moreover, the lung                  lar capabilities that can be classified in the
carcinoma is accounting for nearly 29% of all                  following six functional sets: a) self-sufficien-
cancer-related deaths in both genders, that ex-                cy in growth signals due to mutations in pro-
ceeds the sum of the next three leading causes                 to-oncogenes, b) insensitivity to antiprolifera-
of death due to breast, colon, and prostate can-               tive signals as a result of mutations affecting
cer.4                                                          the tumour suppressor genes, c) evading of
   It is believed that smoking is the primary eti-             apoptosis by up-regulation of antiapoptotic or
ologic agent in more than 80% of lung cancer                   down-regulation of proapoptotic molecules,
patients.5 The other risk factors include, but are             d) limitless replicative potential due to the ac-
not limited to, passive smoking, exposure to                   tivation of telomerase, e) sustained angiogen-
environmental pollutants, occupational expo-                   esis and f) capability for tissue invasion and
sure to chemicals (arsenic, asbestos, chromi-                  capability for dissemination into distant sites
um, nickel and vinyl chloride) and to the natu-                (metastasis).11 Those molecular alterations
ral radioactive gas radon.2 Genetic predisposi-                can occur at the level of gene up-regulation or
tion, especially polymorphisms of the tumor                    down-regulation, DNA sequence changes
suppressor genes and the allelic variants of the               (point mutations), loss of heterozygosity (i.e.,
genes involved in detoxification, are implicated               deletion of one copy of allelic DNA se-
into the susceptibility to the disease.6                       quences), DNA segment amplification or
   Based on the histopathological classifica-                  whole chromosome gains or losses with the
tion (WHO, 1977), lung cancer is divided into                  simultaneous genomic instability and alter-
two main types: non–small cell (NSCLC) and                     ations in microsatellite DNA.12,13
small cell lung cancer (SCLC), which are delin-                   The advances in molecular biology and ge-
eated by their biological and clinical features.               netics, including the modern microarray tech-
Furthermore, NSCLC consists of several sub-                    nology and rapid sequencing techniques,
types, predominantly adenocarcinoma, squa-                     have enabled a remarkable progress into elu-
mous-cell carcinoma, and large-cell carcinoma.                 cidating the lung cancer ethiopathogenesis.
SCLC is a distinct clinicopathological entity                  Numerous studies suggest that more than 20
with neuroendocrine pathophysiologic fea-                      different genetic and epigenetic alterations
tures and characteristic microscopic morphol-                  are accumulating during the pathogenesis of
ogy.7 SCLC represents roughly 20% of all pul-                  clinically evident pulmonary cancers as a
monary cancers. The histologic distinction be-                 clonal, multistep process.14-16 Thus far, the
tween NSCLC and SCLC is clinically extreme-                    most investigated alterations are the inactiva-
ly important. There are considerable differ-                   tional mutations and losses of tumor sup-
ences between those two groups in both, ther-                  pressor genes and overexpression of growth-
apeutic approach and prognosis of the disease.                 promoting oncogenes. More recently, the ac-
Recently, molecular classification of lung car-                quired epigenetic inactivation of tumor sup-
cinomas has been made using mRNA expres-                       pressor genes by promoter hypermethylation
sion profiling by microarray technology.8-10                   has been recognized. The early clonal genetic
                                                               abnormalities that occur in preneoplastic
                                                               bronchial epithelium damaged by smoking or
       Molecular biology of lung cancer                        other carcinogenes are being identified. The
                                                               molecular distinctions between SCLC and
It is generally accepted that the pathogenesis                 NSCLC, as well as between tumors with dif-
of human cancer involves the accumulation                      ferent clinical outcomes have been described.

Radiol Oncol 2005; 39(3): 197-210.
                               Panov SZ / Molecular biology of the lung cancer                                199


These investigations lead to the “hallmarks of           apoptosis inhibition.20 EGFR is overex-
lung cancer”.3 It is realistic to expect that the        pressed in the advanced NSCLC, and is asso-
molecular and cell culture-based investiga-              ciated with the poor survival and resistance
tions will lead to discoveries of new clinical           to chemotherapeutic agents, including cis-
applications with the potential to provide               platin. The results of different studies investi-
new avenues for early diagnosis, risk assess-            gating the prognostic value of EGFR expres-
ment, prevention, and most important, new                sion in lung cancer are contradictory.3
more effective treatment approaches for the              However, since EGFR expression is clearly in-
lung cancer patients.                                    volved in the lung cancer pathogenesis, this
                                                         molecule is an attractive target of different
                                                         therapeutic approaches.21 Few EGFR in-
      Growth stimulation by oncogenes                    hibitors (CP358774, ZD1839-Iressa and
                                                         OSI774) are under intensive clinical trials in
Protein-tyrosine kinases (PTKs) are vital reg-           lung cancer patients.3
ulators of intracellular signal-transduction                 HER-2/neu (ErbB-2) gene is located on
pathways that mediate development and cell-              chromosome 17p21 and encodes for a 185-
to-cell communication. Their activity is nor-            kDa transmembrane glycoprotein (p185HER-
mally firmly controlled and regulated.                   2/neu) that has high homology with EGFR.

Disturbances in the PTK signaling resulting              HER-2/neu is overexpressed in about 30% of
from mutations and other genetic alterations             NSCLCs, particularly in adenocarcinomas
contribute to the malignant transformation.              and is associated with multiple drug resist-
A number of growth factors and their recep-              ance phenotype and high prevalence of
tors are expressed by lung cancer cells or               metastases.3 A point mutation resulting in
their neighboring stromal cells, thus produc-            the substitution of the amino acid residue 664
ing autocrine or paracrine growth stimulation            from valine to glutamic acid is commonly
loops. Several are encoded for by proto-onco-            found, and this mutation contributes to the
genes which become activated in the course               malignant transform of affected cells.
of the lung cancer development.3 The overex-             Alterations and amplifications of HER-2/neu
pression of cell cycle regulatory proteins such          gene have been reported in NSCLC.20
as cyclin D1,17 cyclin E,18 and cyclin B1,19 en-         Chemotherapy combined with trastuzumab
hance the cell proliferation, decrease the cel-          (Herceptin), a monoclonal antibody against
lular apoptotic potential and are commonly               the HER2/neu receptor is now under clinical
found in NSCLC tumor specimen.                           trials.3
   Epidermal growth factor receptor (EGFR),                  MYC proto-oncogene belongs to a family
also called ErbB-1, is the member of a sub-              of related genes (c-MYC, N-MYC, L-MYC)
family of closely related proteins. After lig-           which encode transcription factors that acti-
and-binding, the intracellular tyrosine kinase           vate genes involved in the growth control and
domain of the EGFR receptor is activated and             apoptosis. The MYC phosphoproteins are lo-
undertakes autophosphorylation, which initi-             calized in the nucleus.22 The transcriptional
ates a cascade of intracellular events. A                regulation by MYC proteins is mediated by
downstream signaling pathway involves the                heterodimerizing with partner proteins such
activation of p21-Ras and mitogen-activated              as MAX, MAD or MX11.23 MYC-MAX het-
protein kinases (MAPKs). EGFR signaling is               erodimer binds to specific DNA sequences
critical for the normal cell proliferation, but          named E-box elements in the neighborhood
its deregulation is crucial for cancer patho-            of promoters of downstream target genes and
genesis, neoangiogenesis, metastasis, and                activate their transcription. Histone acetylase

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200                                  Panov SZ / Molecular biology of the lung cancer



is activated and leads to alterations in chro-                 the plasma membrane, where they can effec-
matin structure, which, in turn, modulate the                  tively interact with their upstream activators
gene transcription. On the other hand, the                     and downstream targets. In active state RAS
MYC-MAX complex represses a transcrip-                         proteins binds to guanosine triphosphate
tional activation. MAX can bind MAD and                        (GTP) and through the intrinsic GTPase ac-
MX11 proteins to repress transcription, an-                    tivity and conformational change of RAS, the
tagonize MYC, and promote cellular differen-                   GTP hydrolyze to guanine diphosphate
tiation.20 The molecular abnormalities involv-                 (GDP) and after interacting with its substrate
ing the MYC genes or their transcriptional                     Raf1, RAS returns to the inactive state. The
deregulation were found to be an important                     cell proliferation signal is subsequently trans-
molecular mechanism in the pathogenesis of                     mitted by a cascade of RAS-dependent kinas-
human lung cancers.23 The most frequent ab-                    es, activating the MAPK, which translocate to
normality involving MYC members in lung                        the nucleus and initiate transcription
cancer is gene amplification or gene overex-                   factors.20 This signal transduction pathway is
pression without amplification. The overex-                    sometimes called SOS-Ras-Raf-MAPK mito-
pression of a MYC gene, with or without am-                    genic cascade.11 In malignant cells, the point
plification, occurs in 80 to 90% of SCLCs.22                   mutation in the RAS gene can make the RAS
In contrast to SCLC, the amplification of the                  protein defective in the intrinsic GTPase ac-
MYC gene occurs only in approximately 10%                      tivity that becomes locked into the growth
of NSCLC samples. However, MYC overex-                         stimulatory GTP-bound form, constantly
pression without MYC gene amplification oc-                    sending the signal stimulating cell prolifera-
curs in over 50% of NSCLC investigated spec-                   tion signals to the nucleus.25 RAS mutations
imens.22 MYC gene overexpression has been                      are very rare or absent in SCLC, but can be
identified to be a late event in lung cancer                   identified in 15-20% of NSCLC. Up to 50% of
pathogenesis in the vast majority of SCLCs.20                  the lung adenocarcinomas carry RAS muta-
Lung tumor cell lines established from                         tions,26 usually affecting codon 12 of KRAS
metastatic tumors have a high frequency of                     (85% of cases), and rarely codon 13 of HRAS,
MYC amplification, and this probably ex-                       or codon 61 of NRAS gene.23 The majority (up
plains the correlation of MYC amplification                    to 70%) of these mutations are G→T trans-
with a poor clinical prognosis.24 The anti-                    versions that are induced by benzopyrene di-
sense oligonucleotides therapy models direct-                  ethyloxide (BPDE), nitrosamines and other
ed at downregulating MYC expression show                       DNA adducts-forming agents that are present
encouraging results in cell culture.3                          in the tobacco smoke. It is believed that this
   The dominant RAS proto-oncogene is ex-                      is the reason for the correlation between
tremely important for the transduction of the                  smoking history and the frequency of KRAS
growth-promoting signals from the mem-                         mutations in NSCLC samples which are asso-
brane to the nucleus and consequently for the                  ciated with poor prognosis.27 Few clinical tri-
cellular proliferation. The RAS family of                      als are conducted: using vaccination with mu-
genes includes: the HRAS gene (homologous                      tant KRAS peptides, by suppression of the
to the oncogene of the Harvey rat sarcoma                      mutant RAS gene using antisense oligonu-
virus), the KRAS2 gene (homologous to the                      cleotides, or by inhibition of the farnesylation
oncogene of the Kirsten rat sarcoma virus)                     of the RAS protein that is necessary for its ac-
and the NRAS gene (initially cloned from hu-                   tivation.3
man neuroblastoma cells). The RAS genes                            The distinguishing feature of SCLC tumors
code for four highly homologous 21 kDa pro-                    is the production and release of a broad range
teins called p21 anchored to the inner side of                 of neuropeptides from the neoplastic cells.

Radiol Oncol 2005; 39(3): 197-210.
                               Panov SZ / Molecular biology of the lung cancer                                201


Angiotensin, bombesin, insulin-like growth               ty of histopathological preneoplastic/preinva-
factor 1, vasopressin, serotonin, and sub-               sive grades. There are a number of other can-
stance P are among the best studied signal               didate tumor suppressor genes located at 3p
molecules released by SCLC cells.28 These                and their allelic loss may probably be the ear-
peptides act as ligands for high-affinity re-            liest acquired genetic abnormality in the lung
ceptors on the tumor cell surface, and their             cancer pathogenesis.3,30
binding consequently activate the G-protein                 FHIT is a tumor-suppressor gene located at
coupled receptors enabling a further intracel-           3p14.2, coding for a dinucleoside 5’, 5’’’-P1-
lular transmission of the proliferative signal.          P3-triphosphate hydrolase protein product
By this, SCLC cells are self-stimulating the             (often denoted as pFHIT). The loss of the
growth by autocrine and paracrine manner.                gene results in the accumulation of diadeno-
                                                         sine tetraphosphate, thus stimulating DNA
                                                         synthesis and cell proliferation. A decreased
     Insensitivity to anti-growth signals:               expression of FHIT has been found in 49% of
          tumor suppressor genes                         NSCLC specimen by immunochemistry.
                                                         pFHIT expression is significantly reduced in a
Tumor suppressor genes (TSG) play a critical             large number of early-stage NSCLC and pre-
role in cell’s antiproliferative circuitry and are       neoplastic lesions in chronic smokers. The as-
also involved in the cellular response to DNA            sociation between cigarette smoking and
damage and consequent reparation process-                pFHIT expression suggests a role for FHIT in
es. There is a frequent loss of tumor suppres-           the initiation of smoking-related lung car-
sor genes during the pathogenesis and pro-               cinogenesis.20 It was demonstrated that the
gression of lung cancers, as in many epithe-             reintroduction of wild-type FHIT inhibits lung
lial cancers. The inactivation of the tumor              cancer in vitro growth and in vivo tumori-
suppressor genes occurs by loss of one allele            genicity in nude (athymic) mice.23
from the chromosomal locus, termed loss of                  The RARβ. (retinoic acid receptor beta)
heterozygosity (LOH) and damage to the oth-              gene, located at 3p24 is a strong TSG candi-
er allele by gene mutation or the epigenetic             date. Low or absent RARβ. expression was
hypermethylation of its promoter. The chro-              detected with high frequency in lung cancer
mosomal regions that where found to be most              cell lines and primary lung tumours.23 It ap-
frequently affected by LOH in lung carcino-              pears to result from the aberrant promoter
mas are 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16 TSG lo-          methylation of the RARβ and was observed in
cus), 9q, 10p, 10q, 13q (RB-retinoblastoma lo-           approximately 40% of primary SCLCs.
cus), 15q, 17p (p53 locus), 18q, 19p, Xp, and               The TP53 tumor-suppressor gene (p53) is
Xq.3 The allelic loss at several loci on the             located at chromosome arm 17p13.1 and en-
chromosome arm 3p is one of the most fre-                codes a 53 kDa nuclear protein that acts as a
quent and earliest genetic events in lung can-           DNA-binding, sequence-specific transcrip-
cer pathogenesis found in up to 96% of carci-            tion factor that activates the expression of
nomas and 78% of preneoplastic bronchoep-                genes engaged in promoting growth arrest in
ithelial lesions.29 The high frequencies of              the G1 phase or cell death in response to the
LOH and frequent homozygous deletions                    genotoxic stress.31 Thus, p53 has a role of
found in many lung cancer cell lines and tu-             “guardian of the genome”, maintaining the
mor samples suggest that few potential tumor             genome integrity during the cellular stress
suppressor genes reside at this chromosome               from DNA damage, hypoxia, and activated
region.23 Moreover, the frequency and size of            oncogenes. Also, p53 prevents cells with
the allelic loss of 3p correlate with the severi-        damaged DNA from undergoing mitosis

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202                                  Panov SZ / Molecular biology of the lung cancer



when they enter the G2 phase. p53 blocks                       tween the cell differentiation and prolifera-
cells at the G2 checkpoint, at least partially,                tion. The phosphorylation status of the RB
by inhibition of cdc2, the cyclin-dependent                    protein and its interaction with transcription
kinase required to enter mitosis. The ability                  factor E2F is most important for the regula-
of p53 to inhibit cellular proliferation or to in-             tion of G0/G1 cell cycle transition. When RB
duce apoptosis is suppressed by HDM2 pro-                      is dephosphorylated, it suppresses the G1 to
tein product, the human homologue of the                       S phase transition.32 During G1 phase, cyclin
murine double minute 2 (MDM2). This pro-                       D1 is associated with cyclin-dependent–ki-
tein blocks p53 regulation of target genes and                 nases CDK2 and CDK4 that results in phos-
enhances its proteasome dependent degrada-                     phorylation and activation of RB. Hypo-
tion.31 On the other hand, p53 upregulates                     phosphorylated RB binds the E2F transcrip-
the expression of HDM2 by directly binding                     tion factor, thus blocking the transcription of
and activating the HDM2 promoter and thus                      genes regulating the cell cycle. On the con-
p53 is downregulating its own expression.                      trary, when RB is phosphorylated, E2F disso-
This autoregulatory loop keeps p53 at virtual-                 ciates and activates the transcription, thus fa-
ly undetectable levels in normal cells.3                       cilitating S phase entry.23 Abnormalities of
Missense mutations (mainly G→T transver-                       the RB gene in lung cancer include deletions,
sions) clustered in the middle of the gene at                  nonsense mutations, pathogenic splicing
codons 157, 245, 248, and 273 abolishes its                    variations and chromosomal deletions. The
tumor suppressing activity and extend the                      disruption of the pRb pathway releases E2Fs
p53 mutant protein half-life that can be easi-                 allowing cell proliferation to proceed and
ly detected by immunohistochemistry. The                       making the cell insensitive to antigrowth fac-
p53 gene mutations in lung cancer have been                    tors that normally function to control a tran-
extensively investigated and were found that                   sition through the G1 phase of the cell cy-
p53 is inactivated in 75% of SCLCs and about                   cle.11 More than 90% of the SCLC and 15-30%
50% of NSCLCs and the frequency of muta-                       of the NSCLC neoplasms have abnormal or
tions correlate with cigarette smoking.20 It is                no RB expression.22 Although RB plays an im-
intriguing that the mutations at codon 157 ap-                 portant role in pulmonary cancer pathogene-
pear to be unique to pulmonary carcinomas,                     sis, pRB status has no prognostic significance
while codon 248 and 273 hot spots mutations                    in NSCLC patients.20
occur in other cancers, e.g., colon, liver, and                    PTEN (Phosphatase Tensin Homolog
prostate.22 Nonsmokers who develop lung                        Deleted on Chromosome Ten) gene is located
cancer have a completely different, almost                     at chromosome 10q23 encodes a lipid phos-
random grouping of p53 mutations.22                            phatase which dephosphorylates PIP3 and
Although the prognostic role of p53 muta-                      posses tumor suppressor activity in vitro and
tions in NSCLC p53 is still under debate,                      in vivo. Mutations or deletions of the PTEN
their presence influences the clinical re-                     gene have been found in a few lung cancer
sponse to cisplatin-based chemotherapy and                     cell lines and tumor samples.23
radiotherapy.3                                                     Transforming growth factor-β (TGF-β) is
    The RB tumor-suppressor gene is located                    multifunctional protein that inhibits the pro-
on chromosome 13q14 and its protein prod-                      liferation of many epithelial cells through
uct is a nuclear phosphoprotein initially iden-                binding with a set of cell receptors. It is a
tified in childhood retinoblastomas. RB pro-                   checkpoint inhibitor involved in the cell cy-
tein cooperates with p53 in the regulation                     cle regulation, causing cells to cease prolifer-
and control of cell cycle progression, the tran-               ation and arrest in G1.22 The reduced levels
scriptional level, and the equilibrium be-                     of TGF-β expression was found in NSCLC

Radiol Oncol 2005; 39(3): 197-210.
                              Panov SZ / Molecular biology of the lung cancer                                203


samples by immunocytochemical staining                  mutated and p16 is intact in SCLC, while p16
studies.                                                expression is disrupted and Rb is usually in-
   Another candidate TSG on chromosome                  tact in NSCLC.22 p19ARF binds to the MDM2-
10q25-26 is DMBT1. It is frequently down                p53 and prevents p53 degradation. The loss
regulated and occasionally homozygously                 of p19ARF is more frequent in lung tumours
deleted in lung cancer.23 The overexpression            with neuroendocrine features.23, 31
or activation of insulin-like growth factor I
receptor (IGF-IR) has been observed in many
human cancers including pulmonary carcino-                               Evading apoptosis
mas. The p16INK4 (also termed CDKN2A) is a
tumor-suppressor gene located on chromo-                Apoptosis or programmed cell death is a ge-
some 9p21 and codes for two proteins trans-             netically controlled process that is essential
lated by alternative mRNA splicing: α-tran-             for tissue remodeling during embryogenesis
script that is translated into p16 (p16INK4) and        and for the maintenance of the homeostatic
β-transcript that is translated into p14ARF             balance of cell numbers during adult life. A
protein. p16 protein that is part of the p16-cy-        deregulation of cell death pathways is impli-
clin D1-Cdk4-RB pathway.32 p16 regulates                cated in tumor initiation, progression, and
cell-cycle progression through a G1/S restric-          drug resistance in many human cancers and is
tion point by inhibiting CDK4 and CDK6/cy-              one of the hallmarks of cancer.11, 33 Two major
clin D-mediated phosphorylation of pRB.20               intracellular apoptosis signaling pathways can
The disruption of p16 function results in in-           lead to programmed cell death, the mitochon-
appropriate hyperphosphorylation and,                   drial pathway (intrinsic) and the death recep-
therefore, inactivation of pRB. The overex-             tor (extrinsic) pathway. Mediated by a cascade
pression of the E2F transcription factor up-            of caspase activations and other mediator pro-
regulates p16 expression and inhibits cyclin            teins, both pathways finally lead to the prote-
D-dependent kinase activity, suggesting the             olytic cleavage of a variety of cellular proteins,
presence of a feedback loop. p14ARF protein             induces DNA fragmentation and numerous
binds to and stabilizes HDM2 (MDM2 homo-                morphological changes that are characteristic
logue), increasing its availability of wild-type        of cells undergoing apoptosis. Key genes that
p53. The loss of p14ARF or p53, which are               regulate apoptosis include the p53 tumour
common genetic lesions in lung cancer, per-             suppressor gene and the Bcl-2 gene family.
mits an amplified MYC free opportunity for              Simplified, the BCL-2 family members are ma-
the cell proliferation and transformation.              jor regulators of the apoptotic process, where-
p14ARF appears to bridge a gap between onco-            as caspases are the major executioners.
genic signals and p53 whereby p14ARF-in-                   Bcl-2 (B-cell lymphoma-2) gene was the
duced activation would be critical to move              first oncogene found to function through the
the compromised cell toward apoptosis.22, 31            production of an inhibitor of apoptosis. The
The expression of p16INK4 gene in NSCLCs is             bcl-2 gene family consists of more than 15
frequently altered by abnormal promoter                 members, which either promote or inhibit the
methylation (25% of cases) and homozygous               apoptosis.34,35,36 The bcl-2 gene is located on
deletions or point mutations (10%-40%).23 It            chromosome arm 18q21 and the BCL-2 pro-
was found that the disturbances in both, the            tein product is localized within the outer mi-
p16/pRb and p53 pathways are essential for              tochondrial membrane, endoplasmic reticu-
the enhanced proliferation of NSCLC cell                lum and the nuclear envelope, where it exerts
lines. There is an inverse relation between             anti-apoptotic effect within many cell types.34
p16 and Rb in pulmonary carcinomas: Rb is               Following the apoptotic stimulation, pro-

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204                                  Panov SZ / Molecular biology of the lung cancer



apoptotic proteins are activated through post-                 sion or degradation of the chromosomes.39
transcriptional modifications or changes in                    Due to the inability of the conventional DNA
their conformation. BCL-2 protein forms het-                   polymerases to replicate the 5’-end of linear
erodimers with proapoptotic BCL-2 family                       DNA, telomeres shorten during each cell divi-
members, leading to their inactivation. In ad-                 sion in the normal human somatic cells. This
dition, BCL-2 proteins may interfere with crit-                phenomenon is known as an end-replication
ical steps during the integration of proapop-                  problem. This shortening does not produce
totic signals at the level of mitochondria,                    the loss of the essential genes in which each of
thereby abrogating cytochrome-C release.                       the 46 human chromosomes is capped with
BAX is a BCL-2-related protein which pro-                      long repeats of non-coding DNA sequences
motes apoptosis and is a downstream tran-                      named telomeres. The human telomeres con-
scription target of p53. BCL-2 protein het-                    sists of highly repetitive DNA of tandem se-
erodimerizes with BAX consequently inhibits                    quences TTAGGG)n.40,41 It has been calculat-
apoptosis. Tumor cells often escape apoptosis                  ed that roughly 50–100 bp are lost with each
as the normal physiological response when                      round of cell division.42 Human cells are esti-
challenged by cellular and DNA damage.                         mated to have the potential to undergo on av-
BCL-2 overexpression, detected by immuno-                      erage 50–70 divisions. At this point the cell
histochemistry, was found in 75%-95% of                        growth arrests and enters senescence. A
SCLC tumors, 25%-30% of the squamous cell                      dozen of telomeric proteins are needed to hide
carcinomas and in 10% of adenocarcinomas.37                    the telomeres from the cellular machinery that
The significantly higher incidence of bcl-2                    would normally treat the end of a linear DNA
overexpression in SCLC is unexpected as                        molecule as a broken strand needing repair.43
these tumors are more sensitive to chemother-                  The key telomeric DNA binding proteins are
apeutic agents that induce an apoptotic re-                    the telomeric repeat binding factors,
sponse.3 Interestingly, the expression of BAX                  Tankyrase, heterogeneous nuclear ribonucleo-
and BCL-2 proteins is inversely related in neu-                proteins and few other functionally related
roendocrine cancers. Namely, high BCL-2 and                    proteins. The physiologic maintenance of the
low BAX expression occurs in most SCLC tu-                     telomere requires complex interactions
mors which are also mostly p53 deficient.3 The                 among these proteins, telomeric DNA, and
significance of the bcl-2 expression in lung                   other cellular factors. Telomere integrity is al-
cancer for the overall survival is controversial,              so essential for the chromosome numerical
but bcl-2 expression was found to be associat-                 and positional stability and the telomere
ed with a better prognosis in NSCLC patients                   shortening facilitates the evolution of cancer
that may be associated with the lower tumor                    cells by promoting chromosome end-to-end
vascularization.20,38                                          fusions and the development of aneuploidy.
                                                               The inhibition of telomerase in immortal can-
                                                               cer-cell lines by genetic or pharmacological
        Limitless replicative potential -                      methods results in telomere shortening and
          telomeres and telomerases                            eventually halts cell proliferation.44
                                                                  Telomerase is a specific ribonucleoprotein
Telomeres are specialized heterochromatin                      enzyme complex that elongates and maintains
structures at the end of each chromosome that                  the preexisting telomeres of eukaryotic chro-
serves as protective caps and plays a role in                  mosomes, using an intrinsic RNA molecule as
the maintaining chromosome integrity, re-                      a template and thus is extending the number
versibly represses the transcription of neigh-                 of divisions the cell may undertake.45
boring genes and prevents the end-to-end fu-                   Telomerase holoenzyme contains two main

Radiol Oncol 2005; 39(3): 197-210.
                               Panov SZ / Molecular biology of the lung cancer                                205


components that are essential for the activity:          hibitors regulating endothelial cell prolifera-
hTERT subunit (RNA-directed DNA poly-                    tion and migration are involved in the process
merase, i.e. reverse transcriptase, EC 2.7.7.),          of angiogenesis. Growth factors that have
and hTR, 451-nt RNA chain that serves as a               been shown to stimulate angiogenesis in-
template. The enzyme complex also contains               clude vascular endothelial growth factor
many proteins necessary for the full enzymat-            (VEGF), basic fibroblast growth factor
ic activity that are collectively named as               (bFGF), platelet-derived endothelial cell
telomerase-associated proteins. The gene for             growth factor (PD-EGF) and platelet-derived
the telomerase catalytic subunit hTERT is                growth factor (PDGF).3,23 The productions of
more than 37 kb in length and consists of 16             angiogenesis factors apparently influence the
exons.46 The telomerase activity is absent in            clinical outcome of lung cancer patients.
the majority of normal cells in adult organ-             Namely, the VEGF levels in plasma are corre-
isms, but is increased during the development            lated with the degree of angiogenesis in
and neoplasia.47 Since over 90% of human                 NSCLC and the VEGF expression was found
neoplastic cells have increased telomerase ac-           to be associated with the decreased overall
tivity, it is now generally accepted that this is        and disease-free survival in NSCLC pa-
a one of the cancer hallmarks and extremely              tients.50 Immunochemical studies demon-
frequent and consistent cancer-associated                strated that bFGF is a prognostic indicator in
molecular abnormality. Generally, the telom-             lung adenocarcinoma, since the 5-year sur-
erase expression in malignant tumors is deter-           vival rate was significantly lower for bFGF
mining the capacity for the unlimited prolifer-          positive patients and the more aggressive
ation and thus immortality. A high telomerase            clinical behavior was associated with up-reg-
activity was detected in almost 100% of SCLC             ulation of PDGF.23 In a few clinical trials, im-
and 80% of NSCLC samples using a PCR-                    pressive results were achieved by targeting
based telomeric repeat amplification protocol            VEGF with a “humanized” monoclonal anti-
(TRAP assay). A high telomerase activity in              VEGF antibody. Unfortunately, unexpected
primary NSCLC was found to be associated                 bleeding from large necrotic lung neoplastic
with the increased cell proliferation rates and          masses occurred in the initial trials, but this
advanced pathologic stage.48 Recently, the               should be approachable by a more careful pa-
telomere shortening was found to be an early             tient selection.3
molecular abnormality in bronchioepithelial
carcinogenesis, preceding telomerase expres-
sion and p53/Rb inactivation that occurs in                       Tissue invasion and metastasis
most high-grade preinvasive lesions.49 Since
the telomerase activity is associated with ma-           Molecular mechanisms that lead to the com-
lignant growth, it is a marker for lung cancer           plex ability of the primary lung cancer cells to
detection, and a important target for novel              invade the adjacent tissue and to disseminate
therapeutic approaches.23                                to the distant organs of the patient’s body are
                                                         mainly unknown.3 This process involves
                                                         degradation of the basement membrane, in-
             Tumor angiogenesis                          vasion of the surrounding stroma and the
                                                         blood or lymphatic vessel, ability to growth
New blood vessel growth (neovascularization              without adhesion, angiogenesis, cell prolifer-
or neoangiogenesis) is required for tumors to            ation, and migration.11 Few different genes
sustain and grow beyond 3 mm in diameter                 and their protein products are identified to be
and for metastasis. Different inducers and in-           important for the process of tissue invasion

                                                                                 Radiol Oncol 2005; 39(3): 197-210.
206                                  Panov SZ / Molecular biology of the lung cancer



and metastatic capability of the neoplastic                    spread of the lung cancer cells. The reduced
cells.                                                         expression of laminin α chains (α3 and α5) in
   E-cadherin is a cell adhesion molecule that                 lung neoplastic tissue might result in the
is universally expressed on epithelial cells.                  basal membrane fragmentation necessary for
During the pathogenesis of most epithelial                     the cancer cell invasion.57 Changes in the in-
cancers, E-cadherin function is lost by the                    tegrin expression are found in metastatic
mutational inactivation of the E-cadherin or                   cells in many human neoplasms, including
β-catenin genes, as well as by the transcrip-                  the lung cancer.11 Recently, a study conduct-
tional repression, or enhanced proteolysis.                    ed by Manda and collaborators, identified
This results in reduced E-cadherin-mediated                    that the LAMB3 gene (coding for the laminin
cell-cell adhesion and enables the malignant                   β3 chain, a component of laminin-5) was ex-
cells to invade the tissues and to enter the                   pressed only in NSCLC cells and not in SCLC
blood or lymphatic vessels.51 Therefore, E-                    tumor cells.58 In the same study, the α6β4 in-
cadherin gene is sometimes referred to as the                  tegrin, the specific laminin-5 binding recep-
“suppressor of invasion” gene.52 It was                        tor, was expressed only in NSCLC cells but
demonstrated that E-cadherin loss in lung                      not in SCLC cells. This suggests that laminin-
cancer is associated with the increased metas-                 5 might be a critical microenvironmental fac-
tasis capability.53 A degradation of the basal                 tor for the growth of NSCLC tumours.58
membrane and of the extracellular tissue ma-
trix by proteases is very important for the lo-
cal invasiveness and blood or lymphatic                         Overview of the molecular abnormalities in
metastasis.                                                             lung cancer pathogenesis
   Matrix metalloproteinases (MMPs) are
members of the family of zinc-containing pro-                  The model of lung cancer pathogenesis is de-
teolytic enzymes that facilitate the tumor in-                 picted on the Figure 1 and was developed
vasion, the metastatic capabilities, and the tu-               based on the previous studies.59 The carcino-
mor-related angiogenesis. Conversely, matrix                   gens from the tobacco or other environmental
metalloproteinase inhibitors (MMPIs) have                      pollutants lead to the loss of the 3p21.3 allele
been shown to inhibit tumour growth and                        in thousands of cells on different sites of the
dissemination in preclinical models. It is                     respiratory epithelium. Later, the tumor sup-
therefore not clear why not all lung cancers                   pressor genes located in the 3p21.3 chromo-
express the MMPs and there are conflicting                     some arm become haplo-insufficient. The
reports about the prognostic importance of                     next hit occurs in genes that are critical for the
MMPs expression in lung cancer.54                              cell proliferation, such as RB, p53, p16 or oth-
   It was found that CRMP-1, a protein that                    er genes either by the mutational inactivation
mediates the effect of collapsins, has reduced                 or by the promoter hypermethylation. That
the expression in more aggressive and                          permits a clonal outgrowth of the initially
metastatic lung cancer samples.55 This down-                   transformed cells. Some authors suggest that
regulation is believed to enhance the cell mi-                 the molecular pathogenesis differs significant-
gration ability, which is important for the                    ly between SCLC and NSCLC main tumor
process of metastasis. CRMP and other mem-                     types.30 It is proposed that during the patho-
bers of the collapsin/semaphorin protein                       genesis of the SCLC neoplastic cells arise di-
families might control the cell’s movement.56                  rectly either from normal or hyperplastic ep-
   Laminins and integrins are proteins in-                     ithelial cells without passing through charac-
volved in the adjacent tissue invasion                         teristic preneoplastic intermediate pathologi-
through the basement membrane and further                      cal stages (parallel theory of lung cancer

Radiol Oncol 2005; 39(3): 197-210.
                                Panov SZ / Molecular biology of the lung cancer                                207




Figure 1. Main molecular abnormalities occurring during lung cancer pathogenesis (according to References 59
and 22).


pathogenesis). On the contrary, the NSCLC                 tion of the pathogenesis of this complex dis-
pathogenesis is accompanied with sequential               ease and would led to the advance of novel
morphological changes (sequential theory).                molecular approaches for the early diagnosis
                                                          and therapy of the pulmonary carcinomas.

                  Conclusions
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